The goal of this proposal is to understand the mechanisms by which class III antiarrhythmic drugs prolong action potential duration (APD) and induce early after polarizations (EADs) in cardiac myocytes. Methansulfonanilides are class III antiarrhythmic drugs that prolong cardiac APD by blocking the rapid component of delayed rectifier K+ current, IKr. The recent cloning of HERG, the gene that encodes the human IKr channel, will enable the study of the biophysical basis of channel modulation in greater detail than ever before. This proposal includes five specific aims; 1) to correlate regional variation in the magnitudes of currents with the extent and rate- dependence of APD prolongation by selective class III antiarrhythmic drugs; 2) to determine the mechanism of block of cloned HERG channels by these drugs; 3) to map the binding site on HERG channels for methanesulfonanilides; 4) to determine the mechanism of EAD suppression by an increase in (Mg2+]e in myocytes exposed to selective class III antiarrhythmic drugs; and 5) to determine the relateive roles of IKr and IK1 in [K+]e-dependent enhancement and suppression of EADs induced by these drugs. Our proposed studies will define the cellular mechanisms responsible for two well-known effects of methanesulfonanilides that may limit the antiarrhythmic efficacy of these agents; Firstly, prolongation of APD and QTc by these compounds is attenuated during rapid high heart rates. This rate-dependence may limit the ability of these drugs to terminate tachyarrhythmias. Secondly, excessive prolongation of APD, especially in the setting undesirable features of methanesulfonanilides have been characterized phenomenologically, but athe underlying mechanisms have not been adequately studied. Furthermore, although it is known that EADs are readily suppressed by elevation of extracellular [K+] or [Mg2+], the exact mechanisms are poorly understood. The ionic mechanisms of these three phenomena will be studied in isolated rabbit ventricular myocytes using whole-cell patch clamp techniques. The block of single IKr channels will be studied using heterologously expressed HERG. Our long term goal is to provide a mechanistic rationale for the design of class III antiarrhythmics that retain desired efficacy without undesirable rate-dependence or a propensity to induce EADs.
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